Transmissible spongiform encephalopathies (TSEs or prion disease) are fatal neurodegenerative diseases such as scrapie, Creutzfeldt-Jakob disease (CJD), BSE and chronic wasting disease (CWD). Our project is aimed at understanding and thwarting the accumulation of PrP-res, the abnormal form of prion protein (PrP) that appears to underlie TSE transmission and pathogenesis. Using cell culture and cell-free systems we have 1) identified lysosomotropic amines, cysteine protease inhibitors and certain new PrP peptide fragments as potentially therapeutic new inhibitors of PrP-res formation, 2) described sites of interaction that occur during PrP-res formation, 3) described interactions between normal PrP and PrP-res molecules from different species that may control interspecies transmissibilities of TSEs, 4) determined effects of the membrane attachment of normal PrP on its conversion to PrP-res, 5) assayed the reversibility of PrP-res formation, 6)identified heparan sulfate and serum amyloid P component as stimulators of PrP-res formation, 6) assessed the ability of PrP-res from CWD-infected deer and elk to induce the conversion of normal PrP from humans, cattle and other species to PrP-res and 7) showed that a detergent can induce conformational changes and fibril formation in normal PrP that are reminiscent of PrP-res formation.